The increasing incidence of breast cancer poses a major threat to women's health in the USA and worldwide. How to prevent breast tumorigenesis and to identify new protective factors for the control of breast cancer represents a great challenge in this field. The objectives of this proposal are to unravel a protective role of epidermal fatty acid binding protein (E-FABP) in preventing breast cancer development and to determine the molecular mechanisms by which E-FABP regulates IFNb production and signaling in a specific subset of tumor associated macrophages for antitumor responses. E-FABP, abundantly expressed in macrophages, has been recognized as an important regulator to coordinate cell metabolic and inflammatory pathways. Our preliminary studies demonstrate that E-FABP deficient mice exhibit significant increases in mammary tumor growth and lung metastasis compared to wild type mice, suggesting a protective role of host expression of E-FABP in mammary tumor prevention. Further analysis of E-FABP expression profile indicates that E-FABP is specifically expressed in the subset of F4/80+CD11b+MHCII+CD11c+ cells. Microarray and qPCR experiments show that tumor-induced IFN production and signaling in macrophages are significantly impaired by E-FABP deficiency. Interestingly, IFNb stimulation specifically induces E-FABP upregulation in the process of M1 polarization. Moreover, o-3 fatty acids can greatly enhance E-FABP expression in macrophages. Thus, we hypothesize that E-FABP may regulate macrophage function by promoting IFNb production, signaling and M1-like phenotype switch through enhancing cell lipid metabolism. E-FABP, as a new cancer protective factor, can prevent breast carcinogenesis through promoting macrophage anti-tumor responses. Therefore, modulating E-FABP activity will represent a novel strategy for breast cancer prevention. Specific Aim 1 will determine how E-FABP regulates IFNb production in macrophages. We hypothesize that E-FABP is an unidentified host-derived factor to regulate tumor-induced IFNb production through impacting lipid-mediated signals in specific subsets of macrophages. Specific Aim 2 will determine how E-FABP regulates IFNb signaling to promote anti-tumor responses. We will test the hypothesis that E-FABP-regulated IFNb signaling promotes tumor specific T lymphocyte infiltration and IFNb production, which further upregulates E-FABP expression to facilitate macrophage M1 polarization for antitumor immunity. Specific Aim 3 will address whether host-derived E-FABP protects against breast cancer development in clinically relevant animal models and in humans. We will verify E-FABP as a host-derived protective factor in breast cancer prevention and establish an effective strategy for the control o breast cancer via dietary upregulation of E-FABP. In conclusion, successful completion of this project will reveal E-FABP as a new protective factor in control of breast cancer development and help us develop an effective strategy to prevent breast cancer via targeting E- FABP.